|Title||Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Moccia, A, Srivastava, A, Skidmore, JM, Bernat, JA, Wheeler, M, Chong, JX, Nickerson, D, Bamshad, M, Hefner, MA, Martin, DM, Bielas, SL|
|Date Published||2018 09|
|Keywords||Adolescent, Adult, Carrier Proteins, CHARGE Syndrome, Child, Child, Preschool, Cohort Studies, DNA Helicases, DNA-Binding Proteins, E1A-Associated p300 Protein, Epigenesis, Genetic, Female, Genetic Testing, Humans, Infant, Male, Mutation, Neoplasm Proteins, Phenotype, Repressor Proteins, RNA Splicing Factors|
PURPOSE: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome.
METHODS: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.
RESULTS: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES.
CONCLUSION: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC6034995|
|Grant List||U54 HG006493 / HG / NHGRI NIH HHS / United States |
T32 HL007828 / HL / NHLBI NIH HHS / United States
R01 DC009410 / DC / NIDCD NIH HHS / United States
R00 HD069624 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
T32 GM007544 / GM / NIGMS NIH HHS / United States
R01 DC014456 / DC / NIDCD NIH HHS / United States